CN102617338B - Preparation method of p-trifluoromethyl salicylic acid - Google Patents
Preparation method of p-trifluoromethyl salicylic acid Download PDFInfo
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- CN102617338B CN102617338B CN201210049409.3A CN201210049409A CN102617338B CN 102617338 B CN102617338 B CN 102617338B CN 201210049409 A CN201210049409 A CN 201210049409A CN 102617338 B CN102617338 B CN 102617338B
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Abstract
The invention discloses a preparation method of p-trifluoromethyl salicylic acid. The preparation method includes the following steps of firstly adding m-hydroxybenzotrifluoride and carbonate into a reaction device, feeding carbon dioxide into the reaction device, performing reaction for 20 hours to 24 hours at the temperature from 150 DEG C to 165 DEG C under the pressure of 8atm-12atm, and obtaining a mixture containing 2-hydroxyl-4-trifluoromethyl benzoate; secondly cooling the mixture to the ambient temperature, adding the mixture into hot water at the temperature from 60 DEG C to 90 DEG C to dissolve, cooling the solution to the ambient temperature, and subjecting the solution to extraction; and thirdly, adding acid to an extract solution so that the pH is within a range of 2 to 4, sequentially subjecting the extract solution to filtering, washing and recrystallization, and obtaining the p-trifluoromethyl salicylic acid. According to the preparation method of the p-trifluoromethyl salicylic acid, reaction pressure and reaction temperature are decreased, so that reaction time is greatly shortened, and the yield can reach over 90%.
Description
Technical field
The present invention relates to a kind of preparation method of Drugs Containing Fluorine intermediate, be specifically related to a kind of to the salicylic preparation method of trifluoromethyl.
Background technology
To trifluoromethyl Whitfield's ointment, be agricultural chemicals and medical critical materials and intermediate.
The embodiment 1 of american documentation literature US4110442 discloses the preparation method of a kind of 2-hydroxyl-4-trifluoromethylbenzoic acid (to trifluoromethyl Whitfield's ointment).The method is that the Anhydrous potassium carbonate (3mol) of the m-trifluoromethyl phenol of 162.11g (1mol), 414.60g and carbonic acid gas are reacted one week at the temperature of the pressure of 40atm and 190 ℃, after reaction finishes, through aftertreatment, obtain 2-hydroxyl-4-trifluoromethylbenzoic acid.The deficiency of the method is: (1) reaction pressure is up to 40atm, thereby has increased potential safety hazard; (2) reaction times longer, need about one week; (3) yield is lower, only has 65%, is not suitable for large-scale industrialization and produces.
Summary of the invention
The object of the invention is to address the above problem, provide that a kind of reaction times is short, yield is high to the salicylic preparation method of trifluoromethyl.
The technical scheme that realizes the object of the invention is: a kind of to the salicylic preparation method of trifluoromethyl, there are following steps: 1. m-trifluoromethyl phenol and carbonate are joined in reaction unit, then in reaction unit, pass into carbonic acid gas, at the temperature of the pressure of 8atm～12atm and 150 ℃～165 ℃, react 20h～24h, obtain the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt; 2. the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt 1. step being obtained is cooled to envrionment temperature, then join to dissolve in the hot water of 60 ℃～90 ℃ and obtain the solution that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt, this solution is extracted after this solution is cooled to envrionment temperature; 3. 2. step being extracted to the extraction liquid obtaining, with acid, to be adjusted to pH value be 2～4, then filters successively, washing, recrystallization, obtains trifluoromethyl Whitfield's ointment.
Above-mentioned steps 1. in, the mol ratio of m-trifluoromethyl phenol and carbonate and carbonic acid gas is 1: (2.5～3.5): (1.5～2.5).Described carbonate is anhydrous sodium carbonate or Anhydrous potassium carbonate.
Above-mentioned steps 2. in, the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt and the weight ratio of hot water are 1: 5～1: 6.Extracting extraction agent used is ether.
Above-mentioned steps 3. in, described acid is hydrochloric acid or sulfuric acid.The solvent that recrystallization adopts is the mixed solvent of ethanol and water, and wherein the weight ratio of ethanol and water is 1: 1～4: 3.
The positively effect that the present invention has: method of the present invention is by being down to reaction pressure 10atm left and right, temperature of reaction is down to 160 ℃ of left and right, the whole reaction times can be foreshortened to about 1 day like this, greatly improved reaction efficiency, and yield can reach more than 90%, suitability for industrialized scale operation.
Embodiment
(embodiment 1)
The present embodiment the salicylic preparation method of trifluoromethyl is had to following steps:
1. the anhydrous sodium carbonate (3mol) of the m-trifluoromethyl phenol of 162g (1mol) and 318g is joined in autoclave, then in autoclave, pass into carbonic acid gas (about 2mol), under the pressure of 10atm, be slowly warming up to 160 ℃, and react 24h at this temperature, obtain the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid sodium.
2. the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid sodium 1. step being obtained is cooled to (0 ℃～40 ℃ of envrionment temperatures, lower same), then join 3L temperature and be to dissolve in the hot water of 70 ℃ and obtain the solution that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt, this solution is cooled to after envrionment temperature by twice of extracted with diethyl ether.
3. 2. step being extracted to the extraction liquid obtaining, with hydrochloric acid, to be adjusted to pH value be 3, then filter, then use deionized water washing leaching cake, then use ethanol/water mixed solvent (weight ratio is 1: 1) recrystallization secondary, obtain 196g to trifluoromethyl Whitfield's ointment, yield is 95%.
(embodiment 2)
The present embodiment the salicylic preparation method of trifluoromethyl is had to following steps:
1. the anhydrous sodium carbonate (3.5mol) of the m-trifluoromethyl phenol of 162g (1mol) and 318g is joined in autoclave, then in autoclave, pass into carbonic acid gas (about 2.5mol), under the pressure of 12atm, be slowly warming up to 165 ℃, and react 20h at this temperature, obtain the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid sodium.
2. the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid sodium 1. step being obtained is cooled to envrionment temperature, then join 2.8L temperature and be to dissolve in the hot water of 90 ℃ and obtain the solution that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt, this solution is cooled to after envrionment temperature by twice of extracted with diethyl ether.
3. 2. step being extracted to the extraction liquid obtaining, with hydrochloric acid, to be adjusted to pH value be 2.5, then filter, then use deionized water washing leaching cake, then use ethanol/water mixed solvent (weight ratio is 1: 1) recrystallization secondary, obtain 192g to trifluoromethyl Whitfield's ointment, yield is 93%.
(embodiment 3)
The present embodiment the salicylic preparation method of trifluoromethyl is had to following steps:
1. the Anhydrous potassium carbonate (2.5mol) of the m-trifluoromethyl phenol of 162g (1mol) and 345g is joined in autoclave, then in autoclave, pass into carbonic acid gas (about 1.5mol), under the pressure of 8atm, be slowly warming up to 150 ℃, and react 22h at this temperature, obtain the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid sodium.
2. the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid sodium 1. step being obtained is cooled to envrionment temperature, then join 3L temperature and be to dissolve in the hot water of 60 ℃ and obtain the solution that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt, this solution is cooled to after envrionment temperature by twice of extracted with diethyl ether.
3. 2. step being extracted to the extraction liquid obtaining, with sulfuric acid, to be adjusted to pH value be 3.5, then filter, then use deionized water washing leaching cake, then use ethanol/water mixed solvent (weight ratio is 4: 3) recrystallization secondary, obtain 194g to trifluoromethyl Whitfield's ointment, yield is 94%.
Claims (4)
1. to the salicylic preparation method of trifluoromethyl, it is characterized in that thering are following steps:
1. m-trifluoromethyl phenol and carbonate are joined in reaction unit, then in reaction unit, pass into carbonic acid gas, at the temperature of the pressure of 8atm～12atm and 150 ℃～165 ℃, react 20h～24h, obtain the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt; The mol ratio of described m-trifluoromethyl phenol and carbonate and carbonic acid gas is 1: (2.5～3.5): (1.5～2.5);
2. the mixture that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt 1. step being obtained is cooled to envrionment temperature, then join to dissolve in the hot water of 60 ℃～90 ℃ and obtain the solution that contains 2-hydroxyl-4-trifluoromethylbenzoic acid salt, this solution is extracted after this solution is cooled to envrionment temperature; The mixture of the described 2-of containing hydroxyl-4-trifluoromethylbenzoic acid salt and the weight ratio of hot water are 1: 5～1: 6;
3. 2. step being extracted to the extraction liquid obtaining, with acid, to be adjusted to pH value be 2～4, then filters successively, washing, recrystallization, obtains trifluoromethyl Whitfield's ointment; The solvent that recrystallization adopts is the mixed solvent of ethanol and water, and wherein the weight ratio of ethanol and water is 1: 1～4: 3.
2. according to claim 1 to the salicylic preparation method of trifluoromethyl, it is characterized in that: step 1. in, described carbonate is anhydrous sodium carbonate or Anhydrous potassium carbonate.
3. according to claim 1 to the salicylic preparation method of trifluoromethyl, it is characterized in that: step 2. in, extracting extraction agent used is ether.
4. according to claim 1 to the salicylic preparation method of trifluoromethyl, it is characterized in that: step 3. in, described acid is hydrochloric acid or sulfuric acid.
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